ABSTRACT Loss of myelinated axons is a feature of symptomatic Alzheimer's disease (AD). Our research group has also detected degeneration of myelinated axons in the preclinical phase. A major theme of our ongoing work has been to leverage the information derived from measures of myelin and axonal degeneration to improve the understanding of AD. This is a renewal application for ?White matter degeneration: biomarkers in preclinical Alzheimer's Disease?. Participants comprise cognitively unimpaired adults from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention who have been followed longitudinally with neuroimaging and CSF collection. In this renewal application, we propose to continue to follow enrolled participants as well as recruit additional participants to enrich for AD, including cognitively unimpaired biomarker positive participants, individuals with mild cognitive impairment (MCI), and participants with dementia due to AD. Participants will undergo comprehensive neuroimaging every two years. The hypothesis is that that degeneration of myelinated axons is a critical facet of the AD process, and that measures of white matter degeneration (myelin and axonal) can serve as sensitive markers of neurodegeneration in the context of plaque and tangle accumulation. We will examine measures of axons, including the primary measures neurofilament light protein in CSF and blood, and neurite density derived from multi-shell diffusion MRI. We will also evaluate myelin via CSF biomarkers and quantitative myelin imaging with mcDESPOT MRI. Our three aims are to 1) Define norms for white matter maturation/degeneration and determine the temporal ordering of AD pathology and neurodegeneration, using quantile regression and pattern mixture modeling approaches, 2) Determine the extent to which degeneration of myelinated axons predicts cognitive decline in the context of AD, and 3) Determine the cause(s) of myelin and axonal degeneration. This program of research is expected to inform upon the temporal course of AD development, disease severity, and the development of new treatment strategies.